Criteria for sample inclusion and prioritization

Minimum criteria:

Consent is appropriate for exome, genome and RNA sequencing, as well as individual­ level data sharing via controlled­ access databases (Matchmaker Exchange and dbGaP; additional information on dbGaP available below). If you have any questions about language your consent form needs to contain, please review NIH requirements here.

Sample quantity and quality is sufficient for analysis: 3ug DNA for each sample, concentrated around 50­-100ng/ul [via Pico Green method],​to allow for exome sequencing and whole genome sequencing if needed. Sample volume requirement is no less than 20uL or no more than 600uL. Samples volumes outside this range cannot be accepted for automation purposes.

Likely Mendelian cause: T​he family has a highly penetrant severe and/or early onset phenotype, including those families with phenotypes matching a known but unsolved genetic condition. Families with multiple affected individuals, particularly cases that are consanguineous or large enough to obtain a significant LOD score through linkage, will be prioritized.

Pre­screened for known genetic causes:​ For diseases with known genes, sample has undergone either targeted testing for the major genetic contributors to the phenotype, or exome sequencing.

Likely recessive or d​e novo​ dominant genetic cause:​ Families with multiple affected siblings with unaffected parents, or with a known consanguineous relationship, will be favored over inherited dominant conditions. Probands with a strong suspicion of a de novo cause of disease (embryonic lethal/severe neonatal/pediatric disease) will also be prioritized if parental samples are available for trio analysis.

Multiple cases:​ We will favor submissions for which there are multiple independent cases with the same rare phenotype.

Detailed clinical data and additional samples are available: W​e will favor cases obtained by clinicians in active contact with the patient, for whom detailed medical records are available, and where obtaining additional clinical specimens and data are feasible.

DNA and consent are available from multiple family members: W​e will prioritize cases where DNA samples from additional family members, especially parents and affected relatives, are available for study.

Samples from a disease ­relevant tissue are available for RNA­-seq: W​e will prioritize cases when patient samples from a tissue known to be impacted by the disease phenotype, or a relevant cell line (such as differentiated iPS cells), are available for transcriptome analysis.

Resources are available for detailed follow­up analyses: W​e will favor phenotypes for which there is clinical and biological/laboratory expertise available for the phenotype, and a clear path to targeted testing of candidate genes in other patients with similar phenotypes through local or international collaborations.

Special note on dominant disease pedigrees: ​It is extremely difficult to discover new genes in dominant pedigrees of modest size. We will thus apply generally more stringent criteria in prioritizing these types of families. As a rule of thumb, we will generally only accept pedigrees that are sufficiently large to use linkage to restrict causal variants to 1% of the genome or less. Families with adult onset, complex phenotypes and evidence of incomplete penetrance will generally have a very low priority for the CMG.